Withdrawal in human alcoholics is associated with increased anxiety and depression that can be alleviatedthrough continued drinking. It is belived that these negative affective states constitute a major driving forcefor continued alcohol consumption. Recent data gathered in experimental animals suggests thatendogenous cannabinoids play an important role in regulating anxiety-related behaviors. It is theorized thatthe endocannabinoid system is activated in response to anxiogenic situations, and that this activation servesto dampen neuronal responses contributing to anxiety-like behavior. A growing body of evidence also showsthat ethanol exposure alters brain endocannabinoid (eCB) levels and that chronic ethanol exposure inducespersistent changes in the function of this system. We have recently observed that interstitial levels of theeCB substances anandamide and 2-arachidonoylglycerol (2-AG) are significantly decreased in the centralnucleus of the amygdala (CeA) during acute withdrawal from chronic ethanol exposure. Moreover,resumption of ethanol intake restores 2-AG levels back to pre-withdrawal baseline levels. Based on theproposed role of eCBs as mediators of 'anti-stress' effects, these findings suggest that deficient eCBsignaling in the CeA may underlie a sensitized anxiety-like phenotype thought to contribute to excessiveethanol consumption. The experiments proposed in this Component will employ in vivo neurochemicalmonitoring and behavioral pharmacology to characterize the potential involvement of deficient eCB signalingin the CeA in the motivational effects of ethanol withdrawal. Experiments in the first Specific Aim willcharacterize the effect of ethanol dependence and withdrawal on basal and stress-induced eCB function inthe CeA using in vivo microdialysis. Experiments in the second Specific Aim will utilize behavioral testing tocharacterize the involvement of altered eCB function in the CeA in the increased anxiety-like behavior andexcessive ethanol consumption observed in ethanol-dependent rats. The proposed experiments will evaluateinteractions between eCBs, GABA and glutamate in the CeA and therefore this work is highly related to thework proposed in the Cellular Neurobiology Research Component (Roberto/Siggins). The results obtainedin this research component may provide important new insight into the neural mechanisms that propelalcohol addiction.
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